Lower Cholesterol Naturally

Lower Cholesterol Book

Since Scott Davis released the Beat Cholesterol In 30 Days program, many people used it to learn how to manage their hypercholesterolemia quickly and naturally. Due to his personal fight with the disease and the desire to completely avoid prescription meds, he discovered the most effective techniques to overcome this condition and live longer, happier life. Along with useful information about foods that raise, lower, and help with high cholesterol, the author has a number of helpful chapters, such as a list of foods to avoid to immediately begin lowering cholesterol, knowing the tell tale signs of a heart attack, and healthy recipes which will immediately lower your cholesterol levels. Like all the other Blue Heron Health News promoted health guides, the Beat Cholesterol in 30 Days guidebook will help you achieve better health using an all-natural method. Unlike most prescription drugs, this program ensures a risk-free solution to a reduced cholesterol level in a short span of time. This book will provide you with all there is to know about your silent killer enemy: cholesterol. Read more here...

Natural Cholesterol Guide Summary


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Author: Scott Davis
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My Natural Cholesterol Guide Review

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Ezetimibe and Statins

All of the in vivo data described thus far involve animals fed diets that are substantially higher in fat and cholesterol than the animals' normal chow diet. Despite the substantial activity of ezetimibe and other azetidinone CAIs in these models, none of the compounds tested significantly reduced plasma cholesterol levels in animals fed a normal chow diet. While this was initially a concern, this observation ultimately led to one of the most important aspects of the profile of ezetimibe. In considering the possible reasons for the lack of substantial effect on serum cholesterol in the absence of a high cholesterol diet, Davis reasoned that a CAI might stimulate hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity. This could compensate for a reduced cholesterol load due to inhibition of intestinal cholesterol absorption. If this were the case, then coadministration of a CAI and an HMG-CoA reductase inhibitor should produce an enhanced reduction in serum cholesterol...

Clinical efficacy of hydroxymethylglutarylcoenzyme A reductase inhibitors statins as lowdensity lipoprotein

Statins represent a class of drugs that specifically inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the rate-controlling step in de novo cholesterol biosynthesis.34 Two general classes of statin have been identified the earlier natural product-based statins (mevastatin 1, lovastatin 2, simvastatin 3, pravastatin 4 Figure 7) and the more recent new generation of synthetic statins (atorvastatin 6, fluvastatin 5, cerivastatin 7, rosuvastatin 8, pitavastatin 9 Figure 7). Since their initial discovery in the mid-1970s, multiple statins have been

Safety concerns with statins

Data from animal studies have indicated that pronounced inhibition of cholesterol biosynthesis with high doses of statins induced multiple toxic side effects, including liver enzyme elevations, cataracts, skeletal muscle changes, central nervous system lesions, and certain tumors. However, overall, good safety and tolerability have been observed for the first- and second-generation statins in multiyear clinical trials, and millions of patients have been safely treated with approved doses of these agents. Withdrawals due to adverse events from statins in several multiyear trials were similar to placebo, and the overall incidence of clinically significant adverse events has been quite low. Initial concerns about cataract formation are no longer considered a significant safety issue since several clinical studies monitoring optical lens opacity with the early statins showed that these occurred at the same rate in both statin-treated and placebo groups. Since statins target cholesterol...

Combinations of statins and cholesterol absorption inhibitors

The complementary nature of the two inhibitory mechanisms targeting HMG-CoA reductase and cholesterol absorption suggests that combinations of these agents may have additive or perhaps even synergistic clinical benefits. The first clinical evidence supporting this hypothesis was observed from the additional lipid lowering that could be achieved by using ezetimibe as an add-on therapy to patients who are already taking statins. In this study, 10 mg ezetimibe was given to patients on stable simvastatin therapy. The addition of 10 mg ezetimibe produced an additional 25 reduction in LDLc, indicating a significant synergistic effect.53 In another trial, the addition of 10 mg of ezetimibe to 10 mg atorvastatin achieved > 50 reduction in LDLc, comparable to that seen with an 80 mg dose of atorvastatin alone. Thus, combinations of statins with ezetimibe offer the opportunity to lower significantly the statin dose needed to achieve lipid targets, perhaps with potentially increased safety.

Antioxidants in combination therapy with statins

Several clinical studies have examined antioxidants in combination with various statins. However, no significant beneficial effects in coronary event reduction were achieved by adding vitamin E to simvastatin, pravastatin, or atorvastatin. Notably, in the secondary prevention HDL Atherosclerosis Treatment (HATS) trial, treatments with antioxidants such as vitamin E, vitamin C, and beta-carotene were compared alone or in joint therapy with a combination of simvastatin 3 and niacin 17. In contrast to the lipid-lowering effects and reduction in coronary events observed with the simvastatin niacin combination alone, antioxidants by themselves demonstrated no significant benefit in disease progression and coronary outcomes. However, the beneficial effects of simvastatin niacin on lipid lowering and disease progression were essentially negated when this combination was administered together with antioxidants. Thus, supplementation with antioxidants produced a significant negative outcome...

Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors Statins

Statins specifically target and potently inhibit HMG-CoA reductase, the enzyme that catalyzes mevalonate formation and represents the rate-controlling step in de novo cholesterol biosynthesis (Figure 7).34 No toxic metabolites accumulate as a result of the inhibition of HMG-CoA reductase. HMG is water-soluble and has a number of metabolic pathways available to preclude buildup of this intermediate. However, in vivo, the resulting decrease in mevalonate that occurs from inhibition of HMG-CoA reductase reduces the overall concentration of the steroid pool. In response to this depletion, HMG-CoA reductase expression increases and the hepatic LDLr is upregulated. Approved statins (Figure 7) consist of two subclasses the early first-generation natural product-derived or their related semisynthetic analogs (mevastatin 1, lovastatin 2, simvastatin 3, pravastatin 4), and the newer second- and third-generation synthetic analogs containing a central core aromatic heterocycle (atorvastatin 6,...

Limitations of Low Density Lipoprotein Cholesterol Reduction and Statin Therapy

A clear overall therapeutic benefit has been achieved by lowering LDLc with multiple statins in a subset of patients with established CHD and in primary prevention for high-risk patients. Based upon these positive benefits, statin use has increased such that recent population studies now indicate that in 2002 over 9 of the US adult population were taking some form of statin.77 However, even in controlled clinical settings, the majority of patients fail to reach their projected lipid levels and significant numbers of patients fail to achieve a therapeutic benefit as they continue to experience major coronary events while continuing statin treatment. While coronary event reductions of 25-30 are observed with statins as monotherapy, in secondary prevention trials, nearly 70 of the patients have coronary events that are not avoided. Thus, the search has continued for alternative strategies to lower LDLc or to increase the clinical effectiveness of statins using combination therapies. In...

Combinations of statins with highdensity lipoprotein cholesterolelevating agents

While statin therapy offers a significant therapeutic benefit to the subset of patients that respond to these agents, typically, more than 60 of the statin-treated patients in controlled trials continued to develop cardiovascular disease and failed to experience a therapeutic benefit.34 Most of these nonresponders also had low HDLc levels. Since statins produce only modest increase of HDLc (< 10 ),34 several studies have been conducted to define the potential benefit using statins in combinations with either fibrates or niacin. For example, in the HATS secondary prevention trial, CHD patients with low HDLc (< 31 mgdL_ 1) and normal LDLc levels were treated with a combination of simvastatin and niacin. This combination produced an elevation of 26 in HDLc and a surprising 42 reduction in LDLc. These combined effects on lipids were accompanied by a remarkable 60-90 reduction in CHD events. Since this was a small trial, it would be useful to have these results confirmed in a larger...

Medications for High Cholesterol

Sometimes, despite making changes to their diet, some people continue to have excessive serum cholesterol concentrations. This situation occurs in patients with the nephrotic syndrome, and in those diabetics who have relatively high rates of protein excretion. These high serum cholesterol levels usually can be treated readily in patients with and without renal failure, including people with diabetes, by the administration of a statin drug. These drugs are just as effective in renal disease as in its absence, and no more toxic. They are being used more and more widely, and seem to have other beneficial effects some may reduce the incidence of Alzheimer's disease, and some may reduce the incidence of osteoporosis. Also, muscle damage can occur from statins and can lead to the release into the blood of a protein from damaged muscle, myoglobin, that can cause the kidneys to shut down entirely. This form of acute renal failure has caused the deaths of a number of patients and recently has...


HMG-CoA reductase inhibitors, the so-called statins, are currently being tested in clinical trials for their efficacy as MS therapeutics,34 and for their ability to reduce cholesterol in adolescents with SLE (see Figure 1 and Table 2). Beyond their cholesterol-reducing properties, statins have pleiotropic effects - including anti-inflammatory and neuroprotec-tive properties. In preclinical studies, statins inhibited the onset and progression of disease in EAE by inducing a shift from Th1 (proinflammatory) toward Th2 (anti-inflammatory) cytokine production. In vitro studies suggest that statins inhibit lymphocyte migration across the blood-brain barrier. Further, statins may promote remyelination. In an open-label study of 30 RRMS patients, a simvastatin regimen decreased lesional activity assessed by MRI, and was well tolerated however, it did not affect EDSS scores or yearly relapse rates.35 Statins have many advantages beside being well tolerated, they are administered orally, have...

Cholestyramine resin

koh-less-TEER-ah-meen Alti-Cholestyramine Light M, Lo-Cholest, Novo-Cholaine Light M, PMS-Cholestyramine M, Prevalite, Questran, Questran Light Rx Classification Hypocholesterolemic agent, bile acid sequestrant Action Kinetics Binds sodium cholate (bile salts) in the intestine thus, the principal precursor of cholesterol is not absorbed due to formation of an insoluble complex, which is excreted in the feces. Decreases cholesterol and LDL and either has no effect or increases triglycerides, VLDL, and HDL. Also, itching is relieved as a result of removing irritating bile salts. The antidiarrheal effect results from the binding and removal of bile acids. Onset, to reduce plasma cholesterol Within 24-48 hr, but levels may continue to fall for 1 yr to relieve pruritus 1-3 weeks relief of diarrhea associated with bile acids 24 hr. Cholesterol levels return to pretreatment levels 2-4 weeks after discontinuance. Fat-soluble vitamins (A, D, K) and possibly folic acid may have to be...

The Benefits of Exercise

Along with a healthy diet, exercise is the cornerstone of good health. Physical activity produces a multitude of benefits for your overall health and well-being. Being active helps prevent heart disease and stroke by lowering cholesterol levels and making the heart pump more efficiently. It reduces the risk of dying prematurely, especially of heart disease. Physical activity helps control your weight and prevent obesity, which is a risk factor for high blood pressure and diabetes. Regular exercise also can improve your mood, reduce stress, and relieve depression, not to mention build muscular strength and tone, increase your flexibility, Before beginning any new exercise program, always consult with your doctor if you are over age 40, smoke, or have any risk factors for heart disease, including high blood pressure, a high cholesterol level, diabetes, or a family history of heart disease.

Effects on Lipid Metabolism

The main systemic effect of NDOs so far studied is the effect on lipid metabolism. A few Japanese studies have suggested that feeding rats with fructans leads to modification of blood lipid concentration. Even if controversial studies are reported fructans administration often leads to a decrease in cholesterol and or triglycerides concentration. By using chicory fructooligosaccharide as model substances we have analyzed the influence of feeding rats a diet containing these NDOs on lipidemia in protocols differing in the basal diet, the dose of NDOs, and the duration of the treatment. In all these protocols, the constant effect was a decrease in triglyceride concentration. We hypothesize that such changes in lipid parameters are the consequence of a metabolic adaptation of the liver that might be induced by SCCA. Indeed, hepatocytes isolated from oligofructose fed rats have a reduced capacity to synthesize triglycerides from free fatty acids and acetate and a decreased fatty acyl...

Healthy Diet Guidelines

For example, if you have a high cholesterol level and a family history of heart disease, your doctor probably will recommend that you lower your intake of high-fat foods. On the other hand, if you have a family history of diabetes and are overweight, your doctor probably will advise that you go on a weight-loss diet. A family history of colon cancer might prompt your doctor to advise you to reduce your consumption of red meat. raises your risk for heart disease and stroke. Whole-grain foods that are high in fiber can help improve cholesterol levels and maintain a healthy digestive system. Grains, vegetables, and fruits contain an abundance of nutrients, such as essential vitamins and minerals, many of which have disease-preventing properties. It is important to eat a wide variety of foods to make sure that you are consuming as many of these nutrients as possible.

Antihyperlipidemic Agentshmgcoa Reductase Inhibitors

Atorvastatin calcium Cerivastatin sodium Fluvastatin sodium Lovastatin Pravastatin sodium Simvastatin General Statement The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults has developed guidelines for the treatment of high cholesterol and LDL in adults. Cholesterol levels less than 200 mg dL are desirable. Cholesterol levels between 200 and 239 mg dL are considered borderline-high while levels greater than 240 mg dL are considered high. With respect to LDL, levels less than 130 mg dL are considered desirable while levels between 130 and 159 md dL are considered borderline-high and levels greater than 160 mg dL are considered high. Depending on the levels of cholesterol and LDL and the number of risk factors present for CAD, the provider will develop a treatment regimen. Action Kinetics The HMG-CoA re-ductase inhibitors competitively inhibit HMG-CoA reductase this enzyme catalyzes the early rate-limiting...

Epidemiologic Studies

It is well established that LDL and total cholesterol levels are correlated according to the exponential curve with the risk of CHD. Simultaneously, there is a negative correlation between high-density lipoprotein (HDL) cholesterol and Studies performed by Sacks et al. (5) and other investigators (6) demonstrate that total, very low-density lipoprotein (VLDL) and LDL cholesterol levels are significantly higher in nonvegetarians than in matched vegetarian controls. Although the HDL-cholesterol levels also are higher in nonvegetarians, the ratio of HDL cholesterol to total cholesterol is significantly lower compared to vegetarians. Additionally, blood triglyceride levels in nonvegetarians are significantly higher than in vegetarians. Simultaneously, the prevalence of CHD in nonvegetar-ians is higher than in vegetarians (7).

Clinical and Metabolic Studies

It should be mentioned that Hillman et al. (14) demonstrated the consumption of diet supplemented with lignin by persons with hypercholesterolemia is associated with a decrease of total cholesterol concentration in the blood. However, in persons without disorders of lipid metabolism lignin has no such effect. Studies performed in vitro demonstrate that lignin binds bile acids (15). The hypocholesterolemic action of lignin may be the result of binding bile acids in the intestinal lumen. This mechanism is similar to cholestyramine or plant sterols that have a marked hypocholesterolemic effect in persons with hypercholesterol-emia (16). Although different doses of fiber were used in these separate studies it appears from these summaries that the water insoluble components of dietary fiber are relatively ineffective in lowering the total cholesterol concentration in blood in humans, while the water soluble components are moderately effective. added to the diet as purified preparations of...

Lipid Droplets Hyaline Cartilage

Oo Paraplasmic substances (cell inclusions, stored materials) are either derived ID from metabolic activities (storage materials) or from the enclosure of dead substances (metabolic residue or phagocytosed materials ). Carbohydrates, proteins, fat (mostly triglycerides), ferritin (iron storage particles) and pigments are among the most important paraplasmic inclusions. This figure shows four isogenous cartilage cells (two chondrons or territories) with fat droplets of different sizes. These fat droplets (stained red) are characteristic of mature chondrocytes (see Fig.61). The cell nuclei are stained blue. There is a narrow border between the cartilage cells, which stands out because of its high refractive index. This is the cartilage cell capsule , which is part of the territorial extracellular matrix (see Figs. 193-198).

Roles of Transporters in Pharmacokinetics

Body And Drug Absorption Excretion

This huge network of hepatobiliary transporters can give rise to variations in drug disposition between individuals by modulating the uptake or the exit of drugs and their metabolites from hepatocytes. A change in hepatic uptake may have clinical consequences. It may modulate the pharmacological activity of drugs that act via the intrahepatocellular transduction pathways, it may cause hepatotoxicity, or give rise to drug-drug interactions. The concentration of the cholesterol-lowering HMGCoA inhibitors in hepatocytes must be adequate for their pharmacological activity, and most of the statins (e.g., pravastatin, simvastatin, lovastatin, cerivastatin, and pitavastatin) enter hepatocytes via OATP1B1, and to a lesser degree via OAT1B3.131 Recently identified genetic polymorphisms like the SLCO1B3 haplotype *17 are associated with reduced statin clearance by the liver and lower concentrations in hepatocytes they thus have less effect on cholesterol synthesis.132 Large-scale clinical...

Lipid Droplets Exocrine Gland Cells

Harderian (orbital) gland from a rabbit. Several lipid droplets of different sizes H from an exocrine gland cell (section) after freeze-etching. Freeze-fracture makes it possible to examine cells by electron microscopy without fixation. This special procedure circumvents both the removal of water from the tissue and embedding in synthetic resin. Freeze-etching often brings out different structural properties for individual lipid droplets in different fracture planes H. These structures hold clues to the lipid composition. Lipids are predominantly stored as triglycerides, with cholesterol esters mixed in. In 1694, Johann Jakob Harder described a large gland in the medial upper quadrant of the orbit in the deer. Today, we know that it exists in many mammals and reptiles. Subsequently, this gland became known as the Harderian gland, although its function is still not completely elucidated.

Common Screening Tests

Cholesterol Levels Elevated levels of the fats known as cholesterol in your 89 Cholesterol comes in two forms low-density lipoprotein (LDL), the bad cholesterol, and high-density lipoprotein (HDL), the good cholesterol. Somewhat like a delivery truck, LDL cholesterol carries most of the fat in your blood and deposits the excess inside your artery walls. Like a garbage truck, HDL cholesterol removes fat from your blood, preventing it from building up in your arteries. When testing your cholesterol levels, your doctor measures your total blood cholesterol as well as your LDL and HDL levels by taking a sample of your blood and having it analyzed in a laboratory. A desirable total blood cholesterol level falls under 200 milligrams per deciliter of blood. Doctors consider cholesterol levels above 200 to be high. One in five Americans has a total cholesterol level of 240 or greater, placing that person at risk of a heart attack. Your LDL cholesterol levels should be under 100, and HDL...

Generalization Of Controlled Randomized Trials

In early 1970s, a high cholesterol level was known to be a risk factor for developing coronary heart disease. To confirm this, a trial known as the Lipids Research Clinics Coronary Primary Prevention Trials (CPPT) was initiated by the National Heart, Lung, and Blood Institute to test the hypothesis whether lowering cholesterol can prevent the development of coronary heart disease. In the CPPT trial, a total of 4000 healthy, middle-age males were randomized to receive either the cholesterol-lowering agent cholestyramine or its matching placebo (Lipids Research Clinics Program, 1984). The primary endpoint was the incidence of coronary heart disease after a seven-year follow-up. A statistically significant reduction of 1.7 in 7-year incidence of coronary heart diseases was observed for the cholestyramine group as compared to the placebo (8.1 versus 9.8 ). An expert panel recommended to extrapolate the results for the treatment of high cholesterol in populations that had never been...

The Design of Ezetimibe

Struture Cholestrol Ester

In parallel, we studied the synergistic effect of ezetimibe, along with a statin for lowering cholesterol levels. Thus, ezetimibe (0.007 mgkg_ and lovastatin (5mgkg_ were administered orally to two different sets of chow-fed dogs for 14 days. Neither ezetimibe nor lovastatin showed significant activity however, the combination showed a dramatic reduction in serum cholesterol levels (Figure 6). Based on all these results, ezetimibe has progressed to the clinic as a monotherapy agent and also in combination with simvastatin. The combination drug, named Vytorin, was jointly developed by Schering-Plough and Merck. Based on all these observations, ezetimibe was advanced alone and also in combination with simvastatin and atorvastatin in the clinic, and the results are presented in Figure 7. In the clinic,10-13 ezetimibe (10 mg) when administered alone reduced serum cholesterol levels by 18.5 , on average, and in combination with simvastatin (10 mg), serum cholesterol levels were reduced by...

Cape myrtle Myrsine africana Myrsinaceae

Aerial parts of this evergreen shrub are collected and used as additives in meat and milk-based soups by the Batemi and Masai of east Africa. Saponin-like compounds contained in Cape myrtle, which forms a significant part of the Masai diet, are believed to inhibit absorption of dietary cholesterol, thus helping the indigenous people, who consume large amounts of meat, to remain healthy. The flowers of this species are also eaten, whereas the fruit is said to be used as a treatment for intestinal worms.

Figure 15 Structure of the cofactor undine5diphosphoaDglucuronic acid 39 UDPGA generic reactions of O and

An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.

Genetic Considerations

Combination of genetics and environment appear to account for the vast majority of cases of CAD. First-degree relatives of CAD patients are at higher risk of developing the disease and developing it earlier than the general population. Over 250 different genes have been implicated in the onset of CAD, making it a prime example of the combination of multiple genes and environment seen in complex disease. Defects in genes involved with LDL metabolism, homocysteine metabolism, and blood pressure regulation have been associated. Other genes that have been linked encode apolipoprotein A1 and glycoprotein IIb IIIa. Familial hypercholesterolemia is due to a defective LDLR and is inherited in an autosomal dominant pattern. LDL levels elevated to values double that of normal are seen in affected persons as early as 2 years of age and signs of CAD can be found by age 30.

Apolipoprotein E Expression in the Adult Brain of Mammals

In the vascular compartment, apoE is found in association with several classes of lipoproteins including chylomicrons, the very low-density lipoprotein (VLDL), and a subclass of the HDL.70 These apoE-containing lipoprotein complexes carry lipids such as cholesterol, cholesterol esters, phospholipids, and triglycerides. Apolipoprotein E serves as a ligand for several cell surface receptors that mediate lipoprotein uptake, and thus apoE participates in lipoprotein metabolism and lipid homeostasis. All known receptors for apoE have been shown to be present in the mammalian brain on one or several cell types, including neurons (for a review, see 71). These receptors are members of a single family and include the low-density lipoprotein (LDL) receptor, the very low-density (VLDL) receptor, the apoER2 receptor, the LDL receptor-related protein (LRP), and the gp330 megalin receptor.

Background and Introduction

ERT gained widespread popularity in the US in the 1960s and early 1970s26-28 and, by 1974, approximately 28 million prescriptions were filled for noncontraceptive use of estrogens. Previous studies have shown that ERT slows the rate of postmenopausal bone loss22,29 and reduces the incidence of osteoporotic fractures,22 and until recently, it was generally believed that ERT might be beneficial for reducing the risk of heart disease.30,31 The idea that ERT might have cardioprotective effects was based on observational studies32-37 which suggested that women who take estrogen have a lower risk of CHD compared to women who do not take estrogen. Previous studies38-40 have shown that estrogen therapy reduces plasma levels of the 'bad cholesterol' low-density lipoproteins (LDL) and increases the levels of the 'good cholesterol' high-density lipoproteins (HDL), changes that are associated with a reduced risk of cardiovascular disease. Estrogen also prevents oxidation of LDL cholesterol, which...

Molecular Actions Of Vitamin E During Lipoprotein Lipid Peroxidation

LDL is a spherical particle of 20 to 22 nm diameter consisting of a molecule of apoprotein B-100 (apo B) embedded in a monolayer surface of polar phospholipids and cholesterol that surrounds a core of neutral cholesteryl esters and triglycerides (Table 9.1). The oxidizability of LDL lipids

Raloxifene and Lipids

Estrogen increases HDL cholesterol levels and decreases LDL cholesterol levels in humans39,171 as well in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor.172 In ovariectomized rats, raloxifene treatment has been shown to reduce serum total cholesterol concentrations,97,173 and this reduction correlates with the extent of raloxifene binding to the estrogen receptor.97,173 These results are not surprising for a 'nonsteroidal antiestrogen,' as the original observations for clomiphene analogs and tamoxifen show (see 8.08 Tamoxifen). Raloxifene may also have cardioprotective effects because of its antioxidant properties. This is important since oxidative modifications of LDL have been implicated in atherogenesisis.174 Raloxifene also appears to have a favorable effect on lipid parameters in postmenopausal women. In the published European trial,78 treatment with raloxifene in a dosage of 30, 60, or 150 mg day_ 1...

Antiinflammatory compounds Statins Dietary cholesterol affects the formation of Ab and accelerates the appearance of AD pathology in mouse models high serum cholesterol and low high-density lipoprotein cholesterol levels are AD risk factors.57 Cholesterol-lowering agents, e.g., statins, are of interest as treatments for AD. These agents inhibit b-hydroxy-b-methyl glutaryl-CoA reductase, a key regulatory enzyme in the cholesterol biosynthetic pathway. Atorvastatin 49, evaluated in an intention-to-treat clinical trial, showed positive benefit in ADAS-cog performance at 6 months.58 An observational study of AD patients treated with lipid-lowering agents, 47 of which were statins, showed a positive benefit (i.e., slower decline) on the MMSE.59 Thus, with further study statins may become standard therapy.

Description Medical Diabetes

The beta cells of the pancreas produce insulin and a protein called C-peptide, which are stored in the secretory granules of the beta cells and are released into the bloodstream as blood glucose levels increase. Insulin transports glucose and amino acids across the membranes of many body cells, particularly muscle and fat cells. It also increases the liver storage of glycogen, the chief carbohydrate storage material, and aids in the metabolism of triglycerides, nucleic acids, and proteins.

Other Selective Estrogen Receptor Modulators

Current interest in new SERM molecules has built on the experience of the prototypes with the goal of enhancing bioavailability and selectivity and decreasing side effects (i.e., breast cancer, uterine cancer, and blood clots). All compounds under study have predominantly antiestrogenic effects in the rodent uterus with virtually no estrogen agonist properties. In order to improve upon the raloxifene pharmacophore, some groups have reported on the effect of modifying the benzothiophene nucleus. Particularly noteworthy were two discoveries made by the chemists at Eli Lilly which improved upon raloxifene.77 One change involved the introduction of a methyl ether on either the 5-OH or the 4'OH position, which resulted in compounds with increased potency in a cholesterol reduction assay in ovariectomized rats.178'179 The other change involved the replacement of the carbonyl 'hinge' with other atoms or groups, including N, CH2, S, and O. The change to the oxygen atom resulted in a compound...

Peroxisome Proliferator Activated Receptora Key Regulator of Fatty Acid Oxidation

PPAR-a is expressed in heart, liver, kidney, and skeletal muscle in which it plays a central role in the regulation of lipid, and especially fatty acid, metabolism (16). PPAR-a target genes participate in the conversion of fatty acids to acyl-coenzyme A derivatives, peroxisome P-oxidation, and apolipoprotein expression (A1, AII, and CIII) (10,17). Reminiscent of the story of PPAR-y, fibrates in clinical use for lowering triglycerides and raising high-density lipoprotein (HDL), namely gemfibrozil (Lopid) and fenofibrate (TriCor), were found to be PPAR-a agonists (18). Many insights into PPAR-a have come from the study of PPAR-a-deficient mice (19). For example, these mice lack

Metabolic derangements that accompany liver failure

Primary biliary cirrhosis middle-aged woman with no risk factors for liver or biliary disease, marked, pruritus, jaundice, and positive antimitochondrial antibodies rest of work-up is negative. Cholestyramine helps with symptoms, but no treatment (other than liver transplantation) is available.

Biology and Atherosclerosis

Consistent with the effects seen in macrophages, PPAR-y agonists repress inflammatory cytokine production in T-lymphocytes (42). In ECs, PPAR-g may decrease adhesion molecule expression although the results are variable (43,44), pointing out a limitation of a field that has depended heavily on synthetic agonists as experimental tools, with all the attendant concerns of pharmacological studies physiological relevance, receptor dependence, dose dependence, and toxicity effects to name a few. One example of the potential complexities involved is evident in the relationship between PPAR-y ligands and plasminogen activator inhibitor 1 (PAI-1) levels. Several reports indicate PPAR-y ligands may increase expression of PAI-1, a pro-coagulant, pro-atherosclerotic response. Other laboratories find a PPAR-y-mediated repression of PAI-1 (45-47). Others report inhibition of PAI-1 expression (48). In humans, PPAR-y ligands clearly appear to decrease circulating PAI-1, although this may be a...

Peroxisome Proliferator Activated Receptora in Vascular Biology Inflammation and Atherosclerosis

The clinical trials using fibrates could be considered in some sense tests of the cardiovascular effects of PPAR-a agonists. In the Veterans Affairs HDL Intervention Trial, patients with a prior history of cardiovascular disease and a relatively average LDL, low HDL, and only modestly elevated triglycerides experienced fewer recurrent cardiac events in response to the fibrate gemfibrozil as compared to placebo (23). It remains both

Glucocorticoid Therapy

With short-term use, glucocorticoids are practically free of adverse effects, even at the highest dosage. Long-term use is likely to cause changes mimicking the signs of Cushing's syndrome (endogenous overproduction of cortisol). Sequelae of the anti-inflammatory action lowered resistance to infection, delayed wound healing, impaired healing of peptic ulcers. Sequelae of exaggerated glucocor-ticoid action a) increased gluconeogen-esis and release of glucose insulin-dependent conversion of glucose to triglycerides (adiposity mainly noticeable in the face, neck, and trunk) steroid-diabetes if insulin release is insufficient b) increased protein catabolism with atrophy of skeletal musculature (thin extremities), osteoporosis, growth retardation in infants, skin atrophy. Sequelae of the intrinsically weak, but now manifest, mineralocorticoid action of cortisol salt and fluid retention, hypertension, edema KCl loss with danger of hypokalemia.

Diabetes and fibrinolysis

Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95) that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96) and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched subjects who had not experienced any manifestations of overt CAD (97). We found that impaired fibrinolysis in subjects with type 2 DM, not only under baseline conditions but also in response to physiological challenge, was attributable to augmented concentrations in blood of circulating PAI-1. Furthermore, obese diabetic subjects exhibited threefold elevations of PAI-1 in blood compared with values in nondiabetic subjects despite tissue-type plasminogen activator (t-PA) values that were virtually...

Mechanisms responsible for the overexpression of pai1 in diabetes

Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo (93,94,96,100-103,106). Triglycerides and their constituents (fatty acids) appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro (105,107-109). Liver steatosis is another determinant of elevated concentrations of PAI-1, perhaps indicative of the response of both to derangements in the tumor necrosis factor signaling pathway (110). Insulin and triglycerides exert a synergistic increase in accumulation of PAI-1 in conditioned media when both are present in pathophysiological concentrations (105). Analogous results are obtained with insulin in combination with very low-density lipoprotein-triglyceride, emulsified triglycerides, or...

Discharge And Home Healthcare Guidelines

I I yperlipoproteinemia is a condition of increased lipids (fats) in the blood that has been caused by an increased rate of synthesis or a decreased rate of lipoprotein breakdown. Because lipopro-teins transport triglycerides and cholesterol in the plasma, an increased level may cause pancreatitis and atherosclerosis. Lipids are a mixed group of biochemical substances that are manufactured by the body or are derived from metabolism of ingested substances. The plasma lipids (cholesterols, triglycerides, phospholipids, and free fatty acids) are derived from dietary sources and lipid synthesis. Cholesterol and triglycerides are implicated in atherogenesis. Hyperlipidemia, an elevation of serum cholesterol or triglycerides, can be primary or secondary to another underlying condition. Lipoprotein elevation, or hyperlipoproteinemia, is described by five specific types types I, II, III, IV, and V (Table 3).

Chemical Biology and Chemical Genomics

Combinatorial biosynthesis has been exploited for many years through natural products. More recently, a number of academic and industrial groups have managed to harness some of these processes to produce new collections of related molecules. Progress is particularly evident in the production of classes of polyketides and nonribosomal peptides that have proven useful in pharmaceutical and agricultural products. Examples include antibiotics such as erythromycin, penicillin, rifamycin, and vancomycin, as well as anticancer drugs, cholesterol-lowering agents, and other important classes of pharmaceuticals. Now it is possible to exploit controlled biological manipulations to effect Claisen-like condensations, cyclizations, decarboxylations, dehydrations, epimerizations, reductions, and other chemistries in order to produce new analogs that would otherwise be very difficult to prepare synthetically (Figure 36).222-223

Effects of Estrogen on Lipids and Lipoproteins

Oral estrogen reduces plasma total and low-density lipoprotein (LDL) cholesterol by 5 -15 , increases high-density lipoprotein (HDL) cholesterol by 10 and reduces lipoprotein(a) Lp(a) levels. A potentially adverse effect of oral estrogen is an increase (20 -25 ) in plasma triglycerides (50). The mechanisms of estrogen actions involve enhanced catabolism and clearance of LDL by increasing the number of LDL (apo-B E) receptors in hepatocytes, decreasing hepatic HDL receptors and reducing activity of hepatic lipase, thereby raising levels of HDL-cholesterol (HDL-C, mostly HDL-C2) and enhancing biliary excretion of cholesterol (59,60). The overall effect, therefore, is to reduce cholesterol accumulation in peripheral tissues and to increase its biliary excretion. In contrast to oral estrogens, the effects of transdermal preparations on serum lipids are negligible, probably related to the absence of a first-pass hepatic effect (61). Progestogens, especially the more androgenic ones, tend...

Genes and the Metabolic Syndrome Complex Trait Genetics

For instance, in certain North American aboriginal communities, such as the Oji-Cree of Ontario, the combined prevalence of impaired glucose tolerance and type 2 diabetes is approximately 40 .40 This development has been inextricably linked with the recent doubling of hospitalizations for coronary heart disease among Oji-Cree, despite declining rates in the general Canadian population.41 Among Oji-Cree adults aged 35 and older, 43 had MetS.42 Furthermore, 8.7 of female Oji-Cree adolescents had MetS, as defined by the NCEP Adult Treatment Panel (ATP) III47 criteria. Increased waist girth and depressed HDL cholesterol were the most prevalent individual components in subjects with MetS. Common functional polymorphisms in genes encoding proteins involved in the renin angiotensin system, the G-protein family (GNB3) and components of triglyceride-rich lipoproteins were each significantly associated with MetS in Oji-Cree adults, especially women.43 Such studies suggest that...

Insights into Metabolic Syndrome Progression from the Monogenic Disorders

Nondiabetic FPLD2 subjects have high plasma insulin, triglycerides, free fatty acids, and CRP, together with low plasma HDL cholesterol and adiponectin long before diabetes developed.43 Thus, the characteristic cluster of biochemical abnormalities precedes the relatively late decompensation of glycemic control among carriers predisposed to lipodystrophy. A similar pattern of progression - i.e., early hyperinsulinemia with dyslipidemia and altered adipocytokines followed by hypertension and finally diabetes - may be important in 'garden-variety' MetS. In both cases, spillover of FFA from adipose tissue and uptake and storage viscerally and in ectopic sites, such as muscle and liver, may be a key inciting pathophysiological event. In FPLD, spillover of free fatty acids occurs because there is an anatomical absence of the peripheral subcutaneous fat buffer. In 'garden-variety' MetS, this spillover occurs because peripheral fat stores become saturated. If this pattern of metabolic...

Management of the Metabolic Syndrome

Finally, because of the heightened risk of vascular disease, MetS patients should receive other broad-spectrum preventive treatments such as aspirin. The targets for lipids and blood pressure should follow guidelines and recommendations for higher-risk patients. The treatment of the atherogenic dyslipidemia in MetS is aimed at correcting the fundamental disturbances - namely reducing plasma triglycerides and raising plasma HDL cholesterol. Among currently available agents, the fibrates, which are PPAR-g agonists, are best at normalizing MetS dyslipidemia. In contrast, statins target LDL cholesterol, but their role in vascular disease prevention is supported by a much wider evidence base. Many clinicians will first choose a statin as dyslipidemia therapy for MetS patients, especially when triglycerides are only mildly elevated. Other treatment alternatives include the judicious use of niacin preparations and also combinations of a fibrate, statin, and or cholesterol absorption...

Primary Nursing Diagnosis

Most patients are diagnosed and treated on an outpatient basis. The goal of treatment is to return the patient to the euthyroid (normal) state and to prevent complications. The treatment of choice is to provide thyroid hormone supplements to correct hormonal deficiencies. Treatment of the elderly patient is approached more cautiously because of higher risk for cardiac complications and toxic effects. The medication should not be given if the pulse rate is greater than 100. The treatment is considered to be life-long, requiring ongoing medical assessment of thyroid function. Polypharmacy is a significant concern for the hypothyroid patient. Several classifications of drugs are affected by the addition of thyroid supplements, including beta blockers, oral anticoagulants, bronchodilators, digitalis preparations, tricyclic antidepressants, and cholesterol-lowering agents.

Fat Intake And Disease

Conversely, diets rich in saturated fats increase the ratio of LDL-cholesterol to HDL-cholesterol increasing the risk of a coronary heart disease incident (9,10). However, it is not quite as simple as it seems because different saturated fats and dietary sources of saturated fat have different influences on the level of LDL-cholesterol (11). For example, dairy products which are high in myristic acid (14 0) appear to increase levels of LDL-cholesterol whereas beef fat, containing palmitic (16 0) and stearic (18 0) acids, do so to a lesser extent and cocoa butter, with a high proportion of stearic acid, increases LDL-choles-terol only slightly. This would strongly indicate that other dietary constituents are interacting and playing a vital role in this process.

Benefits of Glycemic Control

The DCCTand UKPDS demonstrated the benefits of glycemic control on the prevention of diabetic microvascular complications and potential benefit in diabetes-associated CVD. Independently, diabetes is a risk factor for CVD morbidity and mortality equivalent to having pre-existing coronary artery disease. Therefore, the treatment goals for modifiable cardiac risk factors, specifically blood pressure and abnormal lipid levels, are more aggressive in individuals with diabetes55 (Table 5). The ADA recommends a goal blood pressure of < 130 80 mmHg, LDL cholesterol of < 100mgdL_ 1 (< 70mgdL_ 1 in individuals with known coronary artery disease), HDL cholesterol of > 40mgdL_ 1 (> 50 mgdL_ 1 in women), and triglycerides < 150 mgdL_ 1. Low-density lipoprotein (LDL) cholesterol4 Diabetes + coronary heart disease High density lipoprotein (HDL) cholesterol Triglycerides aHbA1C is the primary target for glycemic control. Glycemic goals should be individualized, with certain populations...

HRT and Genetic Factors

Thus the estrogen associated risk for thrombosis may be increased in the presence of the prothrombin 20210 G A variant, the factor V Leiden mutation or platelet antigen-2 polymorphisms (95-97). A common sequence variation of the ER gene is associated with the magnitude of the response of HDL cholesterol levels to HRT in women with coronary disease (19). The same ERP genotype is also related to changes in the levels of SHBG, another index of estrogen action (95). It is also interesting that in the HERS trial high levels of Lp(a), which is largely genetically determined, were an independent risk factor for CHD events in the placebo group. HRT lowered Lp(a) levels and the cardiovascular benefit of HRT was significantly related to the initial Lp(a) levels and the magnitude of the reduction in the level (98). It appears therefore, that genetic factors may also contribute to the net clinical effect of HRT regarding CVD in postmenopausal women.

Alternative Therapies to Hormone Replacement Therapy

Tibolone is a steroid hormone with a progestogen-like structure that is converted to estrogenic and androgenic derivatives in vivo. It improves menopausal symptoms and bone density and potentially has fewer side effects than conventional HRT. Limited human observational data on the cardiovascular effects of tibolone indicate that it reduces triglycerides and Lp(a) levels but also HDL and there is a suggestion that tibolone may not increase thrombotic risk (105). We must await data from clinical trials on definite clinical end-points to establish the vascular effects of tibolone.

Interpretation of the statistical analysis

Look at the results table again, then you can see that above the critical two-tail value Excel has returned the actual probability value for the analysis. This value is 0.5748, i.e. the test has proved there is no significant difference between the two margarine diets that were used, as the level of significance from the analysis is 57.5 per cent. We therefore accept the null hypothesis that there is no difference in the cholesterol levels for the subjects taking the two dietary treatments. Although a significant result has not been obtained, the experiment has not PROVED conclusively that the dietary margarine did not have an effect on serum cholesterol. The experiment was performed once, in a small number of subjects. Although this gives weight to the argument that the diet did not have any effect, the more times the experiment is repeated and a similar result obtained, the more likely it is that the hypothesis is correct. We could also improve upon the design of the experiment by...

Mechanisms of action

When used as monotherapy, acarbose and miglitol are not associated with hypoglycemia or significant weight changes. Blocking the absorption of complex carbohydrates decreases the caloric uptake of the small intestine, but the large intestine compensates to assure that adequate caloric goals are met. a-Glucosidase inhibitors do not significantly affect LDL or HDL cholesterol concentrations, but triglyceride levels decline. These agents may prove to be useful in the management of severe hypertriglyceridemia in both the diabetic and non-diabetic population.

Comparisons of rosiglitazone and pioglitazone

In vitro studies reveal that pioglitazone acts as a PPAR-g and partial PPAR-a agonist, whereas rosiglitazone is only a PPAR-g agonist. This difference may explain their different effects on lipid metabolism.73 Both rosiglitazone and pioglitazone improve HDL cholesterol levels by approximately 10 . Rosiglitazone is associated with an increase in LDL cholesterol concentration of 8-16 , which has not been seen with pioglitazone therapy. On the other hand, pioglitazone is associated with a decrease in triglyceride levels that has not been seen with rosiglitazone. Both agents decrease serum FFA concentrations by approximately 20-30 .

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women.

Effects of HRT on Lipids in Women With Diabetes

Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in triglycerides with oral CEE (149), although one showed a greater increase among women with diabetes Transdermal estradiol combined with oral norethisterone significantly decreases total cholesterol and serum triglycerides without significantly affecting LDL-C and HDL-C Regarding Lp(a), no significant differences were found among the groups studied in the NHANES III survey. However, in a randomized controlled study combined continuous HRT (CEE + MPA) has shown beneficial effects on Lp(a) in postmenopausal...

Dyslipidemia as a Risk Factor for Coronary Heart Disease

While smoking, hypertension, age, obesity, diet, and family history all contribute to CHD, dyslipidemia is one of the most prominent risk factors for this disease. Historically, CHD has often been considered a disease primarily associated with hyperlipidemia, i.e., high plasma cholesterol levels, particularly cholesterol associated with low-density lipoprotein (LDLc).4 Indeed, atherosclerotic plaques taken from heart transplant patients contained significantly higher percentages of cholesterol (19-26 +10 ) than nonatherosclerotic coronary tissue taken from the same donors (4 + 3 ).5

Lipoproteins Composition Structure Function and Lipid Transport

A proper balance between phospholipids and free cholesterol (FC) is required to maintain optimal cell membrane structure and fluidity.9 Many cells maintain their FC membrane requirements through endogenous biosynthesis. Other cells, including both the macrophages and underlying SMC involved in atherosclerotic lesion formation, acquire cholesterol by internalization of FC from lipoproteins. Because of their poor water-solubility, neutral lipids such as triglycerides (TGs), FC, and cholesteryl ester generally are not freely circulating in plasma, but instead are packaged together and assembled into larger lipoprotein particles that have amphipathic lipids and proteins as surface components. These submicroscopic spherical particles contain phospholipid (PL) and FC in the outer layer surrounding a core of neutral lipids, primarily cholesteryl ester and TG, held together by noncovalent forces. The cholesteryl ester found in the lipoprotein core is typically derivatized by saturated fatty...

Polycystic Ovary Syndrome and Cardiovascular Risk

Women with PCOS have higher serum triglycerides, total and LDL cholesterol and lower HDL cholesterol levels than weight-matched regularly menstruating women (190). These findings however, vary and depend on the weight, diet and ethnic background. In a large study of non-Hispanic white women, elevated LDL-C was the predominant lipid abnormality in women with PCOS (191). An additional parameter contributing to the elevated cardiovascular risk is hypertension. Obese women with PCOS have an increased incidence of hypertension and sustained hypertension is threefold more likely in later life in women with PCOS (192). It is not clear whether this increase in hypertension is because of the PCOS status, obesity or both. PAI-1 concentrations in blood are higher in women with PCOS as compared to those not affected. PAI-1 levels have been shown to be positively correlated with triglycerides, basal insulin and abdominal obesity (193). It was shown that impaired fibrinolysis and particularly the...

Low Density Lipoprotein Cholesterol and Coronary Heart Disease Risk

The link between elevated plasma total cholesterol levels, high LDLc, and increased CHD risk has been known from epidemiological studies since the early 1980s. The Framingham Study followed over 5000 males and females, monitoring plasma lipid levels and the incidence of MI. In this cohort, subjects with elevated serum cholesterol ( > 275 mgdL_ 1) had more adverse events whether they were healthy or already had CHD. The prevalence of plasma cholesterol levels above 240 mgdL_ 1 in subjects who experienced an MI was 35-52 in males and 66 in females.24 LDLc levels in this CHD subpopulation were well above 100mgdL_ 1 and were most prevalent at 160mgdL_ 1 Subjects who experienced an MI and had high plasma cholesterol levels were at increased risk for another MI or death from either CHD or other causes. Total cholesterol levels in FH patients exceed twice the normal range, and can reach higher than 500mgdL_ 1 in homozygous populations. LDL catabolism is dramatically lowered in these FH...

Microparticles for Labonachip Applications

Many different companies are presently offering a large choice of different types of microparticles for a number of application protocols including the possibility to be loaded on lab-on-a-chip platforms. Many types of special microparticles are commercially available, for various applications. The microparticles are made from different materials, including polystyrene, silica, melamine, glass, magnetite, carboxymethylcellulose, biodegradable polymers (such as polylactide, poly(d,l-lactide co-glycolide), triglycerides (tristearin), partial glycerides (monostearate), fatty acids (stearic acid), steroids (cholesterol), waxes (cetyl palmitate) and are available in different sizes usually ranging from 100 nm up to 1 mm. Table 6.1 summarizes some of the microparticles commercially available for lab-on-a-chip applications together with their main characteristics. Lipospheres (LS) have been proposed as a new type of fat-based encapsulation system for drug delivery of bioactive compounds...

Low Density Lipoprotein Cholesterol Lowering Agents

Plasma cholesterol levels are determined by the balance between dietary intake, de novo biosynthesis, and reabsorption processes in the gut as well as by biliary clearance and excretion. While the majority of plasma cholesterol concentrations are derived from cellular biosynthesis in the body, primarily in the liver, about one-third is accounted for from absorption after dietary intake. Prior to the late 1980s, few alternatives existed to lower plasma cholesterol levels. While changes in lifestyle and diet were recommended, polymeric resins that sequestered bile acids in the gut, such as cholesteryamine and colestipol, were used to lower LDLc. While these agents were extremely safe due to their lack of systemic absorption, the high doses required for clinical efficacy limited patient compliance. Even at maximal doses of grams per day, these resins only achieved LDLc reductions of no more than 25 . Over the last 25 years, tremendous progress has been made in providing alternatives for...

Clinical efficacy of cholesterol absorption inhibitors as lowdensity lipoprotein cholesterollowering agents

Since dietary intake accounts for up to a third of plasma cholesterol levels and a redundant system in the enterohepatic recirculation is used to reabsorb and conserve cholesterol-derived bile acids and steroidal intermediates, various inhibitors of cholesterol absorption have been explored to identify alternative lipid-lowering agents. Such agents should provide an advantage over a simple low-fat diet and have particular benefit for patients who either do not respond or are unable to tolerate statin therapy. Ezetimibe 10 represents the first cholesterol absorption inhibitor approved for LDLc lowering. In clinical studies, daily doses of 0.25-10 mg of ezetimibe as monotherapy were safe and well-tolerated, and did not alter the plasma concentrations of lipid-soluble vitamins. In this study, ezetimibe dose-dependently lowered plasma LDLc, and the 10 mg dose lowered LDLc by 17-18 in hypercholesterolemic patients after 12 weeks of dosing.52 There was no statistically significant change in...

High Density Lipoprotein Cholesterol Elevating Agents

Epidemiological studies clearly indicate that low HDLc (< 40mgdL_ 1) represents a significant independent risk factor for CHD. While statin therapy effectively lowered LDLc by up to 45 , statins generally produce only very modest increases in HDLc levels, usually less than 10 .34 Currently, only two alternatives are available for treating low HDLc fibrates and niacin-based (Figure 8) therapies. Fibrates increase HDLc by 10-15 , but have a more pronounced effect on TG lowering. Fibrates have been available since the early 1970s. The fibrate mechanism of action

Calendar Time And Information Time

At the planning stage the sample size is usually calculated based on information regarding the expected difference between treatments, its corresponding variability, and the desired statistical power for a predetermined risk of type I error. After the study is initiated, patients are enrolled to receive the treatment for a fixed length of time until he or she reaches either the end of the study or the time of analysis with survival as one of the primary endpoints. The Postmenopausal Estrogen Progestin Interventions (PEPI), for example, is a trial funded by the U.S. National Institutes of Health to evaluate the effects of unopposed estrogen and combined estrogen-progestin therapy on four major cardiovascular disease risk factors in postmenopausal women (Espeland et al., 1995). These four risk factors include plasma HDL-cholesterol, systolic blood pressure, two-hour postoral glucose serum insulin, and plasma fibrinogen. Table 10.5.1 gives the five treatments to be assessed in the PEPI....

Mevastatin and lovastatin

The statin class was first identified in the early 1970s by investigators at Sankyo who discovered that the natural product, compactin (mevastatin 1), isolated from microbial fermentations of Penicillium citrinum in a search for new antimicrobial agents, potently inhibited HMG-CoA reductase and lowered serum cholesterol levels in animals.61 Compactin (Figure 7) also effectively lowered serum total cholesterol and LDLc in heterozygous FH patients. However, development was stopped in 1980 for unknown reasons that may have been related to toxicity issues that were uncovered in longer term animal studies.51

Fibrates as highdensity lipoprotein cholesterolelevating agents

Similarly, in the Veterans Affairs HDL Intervention Trial (VA-HIT), 2531 males with CHD having low HDLc (p40 mgdL _ 1), near-normal LDLc (p 140 mgdL _ 1), and elevated TG (p 300 mgdL _ 1) were treated for an average of 5 years with gemfibrozil.58 In this study, LDLc was not significantly altered, TG was lowered 31 , HDLc was raised 6 , and the combined number of CHD events was lowered 24 (a 2-3 decrease in CHD for every 1 rise in HDLc). In comparison, prospective statin trials showed only about a 1 reduction in CHD risk for every 1 decrease in LDLc (Table 4).34 However, attributing the event reductions observed in the VA-HIT trial exclusively to HDL elevations is confounded by the concomitant reductions in triglycerides. In contrast, no significant reductions in coronary events were observed in patients treated with bezafibrate 16 in the Bezafibrate Infarction Program (BIP) trial.

Low Density Lipoprotein Cholesterol Lowering Agents Cholesterol Absorption Inhibitors

Ezetimibe 10 was discovered as part of a program directed at identifying novel ACAT inhibitors for lipid lowering. These azetidinone leads, although weak as ACAT inhibitors, were efficacious in lowering cholesterol in animals, suggesting that they might work by a different mechanism.71-73 This discovery represents a tour de force in lead optimization, driven primarily by increasing in vivo efficacy by minimizing metabolism, and is in sharp contrast to the more common target-directed discovery approaches employed today. The biochemical target for ezetimibe was unknown at the time that discovery efforts began and has only recently been elucidated.74 Ezetimibe 10 has a long half-life, is suitable for once-a-day oral dosing, is rapidly absorbed, and becomes conjugated as its glucoronide metabolite that is excreted in the bile. This mechanism efficiently delivers ezetimibe to its site of action in the intestine, and recycling in the enterohepatic recirculation further insures that a high...

David M Holtzman Mary Jo LaDu and Anne M Fagan

The intercellular transport of lipids through the aqueous circulatory system as well as within tissues and other body fluids requires the packaging of these hydrophobic molecules into water soluble carriers (lipoproteins) and their regulated targeting to appropriate tissues by receptor-mediated endocytic pathways as well as scavenger receptor-mediated pathways.1 Lipoproteins have been classified into several major groups on the basis of the density at which they float by ultracentrifugation. In the plasma, chylomicrons and very low density lipoproteins (VLDL) are large particles that have a high lipid to protein ratio and are the major carriers of triglycerides. Intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) are intermediate sized particles that are high in cholesterol and cholesteryl esters in humans, LDL are the principal cholesterol transporting lipoproteins in the plasma. High density lipoproteins (HDL) are the smallest particles and contain the highest...

Ileal bile acid transporter IBAT and apical sodiumcodependent bile acid transporter ASBT inhibitors

As an alternative to cholesterol absorption inhibitors, specific inhibitors of the IBAT, also known as the apical co-dependent bile acid transporter are being sought. The IBAT system facilitates the reuptake of bile acids from the intestine, thus conserving the sterol pool. Functionally, an IBAT inhibitor should produce the same physiological effects of LDLc lowering achieved by anionic resins, such as cholestyramine, which sequester bile acids in the gut, without the high grams per day doses that dramatically limit patient compliance with sequesterants. The first entrant in this field, 34 (S-8921 Figure 14), has demonstrated oral efficacy in lowering LDLc with no accompanying change in HDLc at doses as low as 1 mgkg 1 day_ 1.78 Development of 34 has been discontinued as it showed no clinical benefit over existing products.

Parallel Group Designs

To illustrate the application of parallel group designs in clinical trials, consider the clinical development of Glucophage. Table 5.2.1 lists three studies of Glucophage regarding evaluation by monotherapy, combination therapy with insulin, and dose response. For the first study (Dornan et al., 1991), the objective was to test the efficacy and tolerability of Glucophage. This study was an eight-month double-blind placebo-controlled trial of Glu-cophage monotherapy in 60 obese patients with NIDDM. This study had a typical parallel group design with a run-in period. After a dietetic review and a one-month run-in period, patients were stratified according to the levels of glycosylated hemoglobin (HbA1C) concentration and randomized to receive either Glucophage or an identical dose of placebo. The starting dose was one tablet (500 mg) daily increased at weekly intervals to three tablets daily after one month. Thereafter the dose was increased by one tablet daily at weekly intervals to a...

What Is a Good Drug Target

Before addressing this question an understanding of which criteria define a 'good' drug target and how such targets have been discovered historically is instructive. While biologics, such as peptide and antibody-based drugs, address targets as well, the scope of this chapter is confined to the discussion of drug targets addressed by small molecules. A cynic's definition of a good drug target would be a target which is already successfully addressed by a marketed small molecule such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with Lipitor,4 or BCR-abl with Gleevec.5 However apt this definition may be, it is too subjective and relies heavily on circular reasoning. Instead, a pragmatist would define a molecular target as one with a proven crucial role in causation or symptoms of a human disease, which when targeted in the clinic with a small molecule leads to reversal or diminishment of the disease and or symptoms. Again, this definition invokes the requirement of a...

Gender Ethnicracial And Life Span Considerations

MI is the single largest cause of death among American men and women, including white, African American, and Hispanic Latino populations. The risk of MI increases with age, and it occurs most commonly in people older than 45 years of age. MIs also occur in young adults, such as individuals who use cocaine, those who are insulin-dependent diabetics, and those who have hypercholesterolemia and a positive family history for early coronary disease.

Suketu Shah md Alina Gavrila md and Christos S Mantzoros md

Our understanding of the function of fat cells has changed dramatically with the realization of the endocrine function of adipose tissue. Initially thought to serve only as a repository for energy via storage of triglycerides, adipocytes are now known to secrete a variety of proteins with diverse metabolic functions. These proteins include leptin, TNF-a, plasminogen activator inhibitor-1, acylation-stimulating protein, resistin, and adiponectin (1,2). Adiponectin has received much attention for its putative role in diabetes and CVD. Besides being associated with the development of diabetes, it may also have a direct role in modulating inflammation and atherosclerosis and thereby be one of the factors that links obesity to CVD.

J A Sikorski Athero Genics Alpharetta Ga Usa 2007 Elsevier Ltd All Rights Reserved Low-Density Lipoprotein Cholesterol-Lowering Agents 472 Clinical efficacy of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) as low-density lipoprotein cholesterol-lowering agents in patients with coronary Safety concerns with statins 476 Clinical efficacy of cholesterol absorption inhibitors as low-density lipoprotein cholesterol-lowering agents 477 Combinations of statins and cholesterol absorption inhibitors 477 Antioxidants as Monotherapy in Coronary Heart Disease 478 Antioxidants in combination therapy with statins 478 Combinations of statins with high-density lipoprotein cholesterol-elevating agents 479 6.20.5 Current Treatments 480 Low-Density Lipoprotein Cholesterol-Lowering Agents Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitors (Statins) 480 Low-Density Lipoprotein Cholesterol-Lowering Agents Cholesterol Low-Density Lipoprotein...

Unmet Medical Needs

Androgen replacement therapy has been reported to cause water retention, polycythemia, hepatotoxicity, sleep apnea, prostate enlargement, and to reduce HDL cholesterol.3 Hepatic toxicity is associated with derivatives of testosterone rather than pure testosterone. Polycythemia is observed more commonly in males receiving injectable testosterone. Thus, hematocrit should be measured periodically to minimize the risk of polycythemia. HDL cholesterol lowering is more profound with oral methyltestosterone than transdermal or injectable testosterone, but this effect is dose dependent, with higher doses causing more profound lowering of HDL cholesterol. Although testosterone is associated with prostate enlargement and prostate cancer, testosterone replacement therapy is rarely associated with an increase in urinary tract voiding symptoms, leading to cessation of therapy. In addition, prostate cancer surveillance can be done by measurement of PSA during the first 6-month interval after...

Nitrogen Containing Bisphosphonate Inhibition of the Cholesterol Biosynthetic Pathway

Over 15 years ago, it was shown that certain BP derivatives (isoprenoid (phosphinylmethyl) phosphonates) weakly inhibit the cholesterol biosynthetic enzyme squalene synthase.51 The search for more potent inhibitors that might block cholesterol production revealed that the N-BPs incadronate (YM175) and ibandronate potently inhibit squalene synthase.52 Subsequent studies examined the structure-activity relationship (SAR) for inhibition of squalene synthase.53-55 In vivo testing showed that certain compounds suppressed serum cholesterol in rodents.53 Other cholesterol-lowering bisphosphonates were shown to trigger degradation of hydroxymethylglutaryl coenzyme A (HMG-CoA).56-58 In the same context, utility of squalene synthase inhibition by bisphosphonate was also used for the development of an assay to measure zoledronate levels in animals and clinical serum samples.59 Although cholesterol itself is important for osteoclast signaling and survival, the osteoclast relies on low-density...

Nongenomic Actions Extranuclear Actions

Several tissue- and TR isoform-specific compounds have been developed as potential treatments for hypercholesterolemia, obesity, and heart failure reviewed in 96 . In the development of these compounds it is attempted to use information on tissue-specific uptake of the compound. One of the initial compounds was investigated in mice, who subsequently had lower serum cholesterol levels without cardiotoxicity. Recently, several other TH analogs have been described that have compared to TRa. Since thyroid hormone receptors in the liver, isoform-selective affinity for TRp is approximately 90 TRp, and in the heart mostly TRa, these isoform-selective compounds may serve as novel agents to lower serum cholesterol with minimal cardiotoxicity. Recently, KB141 was shown to be a potential treatment for obesity by decreasing body weight via stimulation of metabolic rate and oxygen consumption.

Diabetes and Insulin Resistance

Although not entirely known, the cellular and molecular mechanisms linking adiponectin to improved insulin sensitivity are also likely multifactorial. In rodents, adiponectin administration enhances insulin-stimulated glucose uptake into fat and skeletal muscle cells (49-51). By increasing fatty acid oxidation, adiponectin can also lower circulating free fatty acids (FFAs), which may improve insulin action (51,52). Another important function of adiponectin is enhancement of insulin-induced suppression of hepatic glucose production (53,54). By generating nitric oxide (NO) formation, adiponectin may also augment vascular blood flow to promote glucose uptake (55). Taken together, all these effects could explain why giving adiponectin to mice on a high-fat and high-sucrose diet will induce weight loss and reduction in FFA, triglycerides, and glucose levels (56).

Mechanism of Action at the Cellular Level

The signaling pathways involving geranylgeranylated small GTPases that are affected by bisphosphonates and that lead to osteoclast apoptosis remain to be determined. Perhaps most proximal to the GTPases is the mammalian target of rapamycin (mTOR) ribosomal protein S6 kinase (S6K) signaling pathway.90 Signaling through this path is suppressed when geranylgeranylation is blocked in the osteoclast (Figure 2). Furthermore, specific inhibition of mTOR by rapamycin causes induction of osteoclast apoptosis over a similar time course to that of the N-BPs. Signaling through mTOR represents a relatively novel pathway downstream of receptor activator of NFkb (RANK), tumor necrosis factor alpha (TNF-a), and interleukin-1 (IL-1) signaling in the osteoclast.91,92 Downstream of phosphoinositol-3 kinase, signaling through the Akt kinase to mTOR was originally implicated in maintaining osteoclast survival, putatively through the regulation of protein translation, which itself was shown to be critical...

Results And Discussion

To elucidate more of the so far not fully understood mechanisms behind the effect of treatment with the thia fatty acids, we compared the effect of treatment with thia acids with the sulphur in different positions (Table 1). The main difference between these 16 carbon (17 including the sulphur) fatty acids is their availability for mitochondrial P-oxidation. As already mentioned TTA is blocked for P-oxidation, but can enter the mitochondria, as it is substrate for CPT-I and CPT-II. However, 5-S, 7-S and 9-S can both enter the mitochondria and undergo 1, 2, or 3 cycles of P-oxidation respectively, before they are metabolised into chain-shortened 3-thia fatty acids which cannot be P-oxidised. Evidently, the metabolised forms of 5-S, 7-S and 9-S will accumulate in the mitochondria. In agreement with earlier findings TTA administration lowered plasma triglycerides, 5-S tended to lower plasma triglycerides, but 7-S and 9-S did not effect the plasma triglyceride levels (data not shown). As...

Mechanisms of Renal Dysfunction

Endothelial dysfunction commonly occurs in obesity, type 2 diabetes, and hypertension. The endothelium acts to regulate vascular homeostasis by maintaining a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell proliferation and migration, and inhibition of platelet activation, adhesion, and aggregation.24 Essential hypertension was first recognized to cause endothelial dysfunction early in the last decade where the increase in blood pressure has a direct influence on vascular function independent of other cardiovascular risk factors. Dysfunction of the endothelium could be due to decreased vasodilatory mediators and or increased vasoconstrictor mediators. Factors that lead to reduction of vasodilation and endothelial dysfunction include a reduction in nitric oxide (NO) production, increased oxidative stress, a decrease in NO bioavailability decreased prostacyclin levels, and a reduction of hyperpolarizing factors. Inflammatory responses...

Management of Renal Dysfunction

Aside from the classic treatment of hypertension, an emerging approach to renal dysfunction is the treatment of the components that trigger endothelial dysfunction, e.g., NO bioavailability and oxidative stress. For example, oral treatment with L-arginine, the precursor of NO, reduces blood pressure and improves endothelial dysfunction in hypertensive patients.60 Statins and lipid-lowering drugs improve endothelial dysfunction in hypertensive animal models by enhancing NO levels.61 Antioxidants also can improve endothelial dysfunction in hypertensive animal models. For example, the SOD mimetic tempol decreases hypertension and oxidation stress and improves endothelium-dependent relaxation and kidney damage in hypertensive animal models such as AT-II-infused mice and Dahl salt-sensitive rats.62

Worksite Health Promotion

Health promotion at the worksite covers a wide variety of activities, including exercise and fitness, stress management, smoking cessation, and cholesterol reduction. Specific programs targeting women may include prenatal care, parenting, breast examinations, and mammograms.

Classification Vitamin B complex

Action Kinetics Niacin (nicotinic acid) and niacinamide are water-soluble, heat-resistant vitamins prepared synthetically. Niacin (after conversion to the active niacina-mide) is a component of the coen-zymes nicotinamide-adenine dinu-cleotide and nicotinamide-adenine dinucleotide phosphate, which are essential for oxidation-reduction reactions involved in lipid metabolism, glycogenolysis, and tissue respiration. Deficiency of niacin results in pellagra, the most common symptoms of which are dermatitis, diarrhea, and dementia. In high doses niacin also produces vasodilation. Reduces serum cholesterol and triglycerides in types II, III, IV, and V hy-perlipoproteinemia (mechanism unknown). Peak serum levels 45 min tV2 45 min.

Blood glucose homeostasis

Glucose is produced by glycogenolysis and gluconeogenesis. Dietary glucose intake can be from glucose itself, glucose-containing polysaccharides (starch and glycogen), glucose-containing disaccharides (sucrose, maltose, lactose), sugars readily converted to glucose (fructose), gluconeo-genic amino acids and the glycerol moiety of triglycerides.

Validation of New Methods

Figure 27.4 Sector map display of the MGPS data mining profile for a drug, using a dictionary of medical terms. This display shows the safety profile of cerivastatin, a drug withdrawn from the US market in August 2001 because of reports of fatal rhab-domyolysis, renal failure, and other organ failure 24 . The sector map shows strong signals for several serious muscle events including rhabdomyolysis and for renal failure (note the signals for renal tubular necrosis highlighted in the yellow pop-out note). The strong renal failure signals with this drug were unexpected. In addition, there were huge differences between cerivastatin and other statins regarding the magnitude of the renal failure signals. See color plate.

Free Fatty Acids and Nitric Oxide

Increased levles of free FAs causes increased very LDL production and cholesteryl ester synthesis. The resulting increased triglycerides found in diabetic subjects, coupled with the lower high-density lipoprotein (HDL), have also been associated with endothe-lial dysfunction (134,135).

Parameters of glucose metabolism

Glucose concentration in venous blood Glucose concentration in capillary blood Glucose concentration in plasma Limit for diabetes mellitus in plasma HBAic (glycosylated hemoglobin A) Parameters of lipid metabolism Triglycerides in serum Total cholesterol in serum HDL cholesterol in serum Substances excreted in urine Urea concentration in serum Uric acid concentration in serum Creatinine concentration in serum Bilirubin

Materials And Methods

Case report The patient was first described by Niezen-Koning et al.5 She presented at 36 hours of age with sudden cardiorespiratory insufficiency and extreme hypogly-caemia. Despite treatment with low-fat diet supplemented with medium-chain triglycerides and carnitine she died at 24 month of age.

Inhibitors of AGE Production

Conversely, hyperglycemia, which increases oxidative stress, can convert even elevated levels of NO to peroxynitrite, which is deleterious to vascular function (179). A decrease in oxidative stress can restore vascular function rather than increase the NO supply. Prolonged hyperglycemia and hypercholesterolemia both cause a depletion of tetrahydrobiopterin (BH4), an essential cofactor for NOS, resulting in an uncoupling of eNOS and lowered production of NO (180). Studies using both diabetic animal models (113) and hypercholesterolemic patients (112) have demonstrated that tetrahydrobiopterin

Angiotensin Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been shown both to improve endothelial function and to reduce the development of atherosclerosis in various animal models of hypercholesterolemia (192,193), independent of its BP-lowering effect. Similarly, the Heart Outcomes Prevention Evaluation (HOPE) study has demonstrated the utility of the ACE inhibitor ramipril in preventing cardiovascular events in diabetics (194) although the mechanism of this effect remains obscure. Clinical trials have demonstrated that the ACE inhibitor quinapril improved endothelial function in nondiabetic patients with CAD (195). Studies evaluating the effect of ACE inhibitors on type 1 diabetic subjects have resulted in conflicting conclusions. Two studies have demonstrated that ACE inhibitors have no effect on vascular function in patients with type 1 DM, even after 6 months on the drug (196,197). However, O'Driscoll and colleagues found improvement in endothelial function by ACE inhibition in...

HMG CoA Reductase Inhibitors

Large clinical trials have determined that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) significantly reduce cardiovascular morbidity and mortality. Furthermore, lipid-lowering therapy has been shown to improve endothelial function in several studies (204,205). Attempts to ameliorate the impaired endothelium-dependent vascular relaxation that occurs in diabetic patients with dyslipidemia are few and the results mixed. Impaired endothelium-dependent vasodilation in patients with type 2 DM with dyslipidemia has been reported to improve with fibrate therapy (206) (which lowers the serum triglyceride level) but not with simvastatin (206,207). 66. Clarkson P, et al. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 1996 28(3) 573-579. 77. Gilligan DM, et al. Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation 1994...

Abnormal Blood Cholesterol and Other Lipids

Cholesterol is necessary for a variety of bodily functions including the formation of plasma membranes and as a building block for hormones. Cholesterol is obtained through ingestion and synthesis in the body and is transported throughout the body by LDL and HDL. Elevation in plasma total cholesterol and LDL levels are clearly associated with increased risk of CVD, including CHD and stroke. High blood cholesterol levels are estimated to cause 4.4 million deaths annually that amount to over 18 of strokes and 56 of CHD.7 The current guidelines for plasma cholesterol and other lipids indicate that patients with total cholesterol of > 240 mg dL _ 1 are twice as likely to experience heart disease as a person whose total cholesterol is less than 200mgdL_ 1. Similarly, patients with LDL cholesterol levels of > 190mgdL_ 1 are considered as 'high risk' patients for CVD. In patients with diabetes or existing CHD, the LDL cholesterol level that places an individual at risk decreases to...

Adrenoceptor Antagonists

A-Adrenoceptors are subdivided into two major classes, ai and a2, each of which has three subclasses. Antagonists of a adrenoceptors, e.g., quinazolines (prazosin, doxazosin, and terazosin), are antihypertensive (Figure 2). They are selective for a1-adrenoceptors, but not for any of the three subclasses (a1A, a1B, and a1D) Unlike older a-adrenoceptor antagonists phenoxybenzamine and phentolamine, quinazolines do not increase heart rate. Prazosin was widely used in the treatment of hypertension for a quarter of a century. The onset of action of prazosin is rapid the maximal antihypertensive effect is usually reached within 2 h of oral administration of the drug. An important advantage of prazosin and other quinazolines over thiazides or -adrenoceptor antagonists is their favorable effect on blood lipids they tend to decrease triglycerides and low-density lipoprotein, while increasing high-density lipoprotein cholesterol levels. Terazosin inhibits ex vivo platelet aggregation induced by...

Importance of planned behavioral change

Pitfall 2 Development of an intervention intended to change a behavior for which there is no consensus about the relation to the problem. This can be illustrated by the discussion on cholesterol testing. Only recently has some consensus been reached about the relationship between cholesterol plasma levels and specific cardiovascular health problems. In addition, currently the relationship between diet and cholesterol levels is being questioned. As a result, interventions intended to lower the cholesterol content of diets may have limited effects on health. Changing behaviors which are not unequivocally related to a problem will not be helpful in reducing the problem.

Education as a method of dietary behavioral change

Programs aimed at students were found to impart knowledge, but not to lead to behavioral change. As far as high-risk groups such as patients with diabetes, cancer, kidney problems, high blood pressure, high cholesterol level, and obesity are concerned, maintenance of behavioral change (diet compliance) is the major problem. Mass media nutrition education programs do not yield positive results. Successful nutrition education programs are characterized by interpersonal contact, social support, self-control, and feedback. Adaptation of the intervention to the individual's attitudes and skills is effective. Interventions aimed at groups (e.g., patient groups) and those based on relapse prevention techniques are promising. For example, in the Netherlands, a large number of programs are available, but subsequent evaluation is often lacking. The Way of Life television campaign, intended to combine health education with entertainment, appeared to attract people's attention, and to heighten...

Mechanisms of Foam Cell Formation

Foam cells are the hallmark of the arteriosclerotic process. Diabetes appears to enhance foam cell lesion formation in experimental animals and in humans. In animal models, type 1 diabetes induced by autoimmune-mediated P-cell destruction or by toxins, alloxan, or streptozotocin increases fatty streak formation (98-100). Similarly, in human postmortem studies it has been shown that diabetes accelerates the formation of fatty streaks. The Pathobiological Determinants of Atherosclerosis in Youth study, a study in 3000 youths, ages 15 to 34 years, who died of trauma, showed that youths over 25 years of age with elevated levels of glycated hemoglobin (> 8 ), had significantly more fatty streaks in the right coronary artery than controls even when their lipid profiles were normal (101,102). A recent high-resolution ultrasound in vivo study of common carotid arteries of 11-year-old children with type 1 diabetes showed that these children had an increased intima-media thickness (IMT)...

Quantitativequalitative abnormalities of lipoproteins

VLDL levels has been attributed to increased hepatic production or decreased clearance of VLDL (111) and may be very significant in the development of arteriosclerosis in diabetes and in women (112). HDL levels in diabetes vary with the type of diabetes and, in some groups, with glycemic control. In type 2 diabetic patients, HDL levels are usually low and do not necessarily increase with improved metabolic control (107,110,113). The low HDL levels are secondary to an increased clearance rate by hepatic triglyceride lipase (114). In type 1 diabetic patients it has been shown that HDL cholesterol levels are low during poor glycemic control and increase to normal or above normal when adequate control is attained (108,110,115). Changes with improved glycemic control are less marked in women than in men (108). In type 1 black diabetic women, little association is observed between plasma lipid levels and glycemic control (115). Abnormalities in LDL lipid composition may also lead to altered...

Carbohydrate digestion

* Dietary fat is primarily composed of the triglycerides of long chain (16-18 carbon) fatty acids. Lipolysis (hydrolysis of triglycerides) by pancreatic lipase fatty acid-binding proteins (apoproteins). Re-esterification in the smooth endoplasmic reticulum of fatty acids and beta-monoglycerides to triglycerides through the monoglyceride acylation pathway and the phosphatidic acid pathway. Lipoprotein synthesis and chylomicron formation in the Golgi apparatus. The core of chylomicrons contains triglycerides and cholesterol, and the surface is made up of phospholipids and apoproteins.

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